FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression

Abstract

Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase/Akt pathway, and are key regulators of the cell cycle, apoptosis and response to oxidative stress. FOXOs have been shown to have tumour suppressor function and are important for stem cell maintenance. We have performed a detailed analysis of the transcriptional programme induced in response to Forkhead-box protein O3a (FOXO3a) activation. We observed that FOXO3a activation results in the repression of a large number of nuclear-encoded genes with mitochondrial function. Repression of these genes was mediated by FOXO3a-dependent inhibition of c-Myc. FOXO3a activation also caused a reduction in mitochondrial DNA copy number, expression of mitochondrial proteins, respiratory complexes and mitochondrial respiratory activity. FOXO3a has been previously implicated in the detoxification of reactive oxygen species (ROS) through induction of manganese-containing superoxide dismutase (SOD2). We observed that reduction in ROS levels following FOXO3a activation was independent of SOD2, but required c-Myc inhibition. Hypoxia increases ROS production from the mitochondria, which is required for stabilisation of the hypoxia-inducible factor-1a (HIF-1a). FOXO3a activation blocked the hypoxia-dependent increase in ROS and prevented HIF-1a stabilisation. Our data suggest that FOXO factors regulate mitochondrial activity through inhibition of c-Myc function and alter the hypoxia response. 4 FOXO factors regulate the expression of genes involved in the inhibition of cell cycle progression and induction of apoptosis.5 FOXO also regulates detoxification of reactive oxygen species (ROS) through upregulation of mitochondrial superoxide dismutase (SOD2). 6Mitochondria are central hubs for cellular bioenergetics and are an important source of ROS within mammalian cells. ROS are produced by the respiratory complexes located in the inner mitochondrial membrane. Mitochondrial ROS can cause oxidative damage to the mitochondrial DNA (mtDNA), proteins and lipids, but are also involved in signalling from the mitochondria to the cytoplasm. The regulation of mitochondrial function is crucial for the survival of both normal and cancer cells. The mitochondrial genome encodes only 13 proteins. The majority of proteins required for the maintenance of the structure and function of mitochondria are nuclear encoded. The expression of these genes is regulated by a network of transcription factors, including the nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and the oestrogen-related receptor-a (ERRa). These are bound to and activated by cofactors, peroxisome proliferator-activated receptor gamma co-activator-1a and 1b (PGC1a and PGC1b) and PGC-related 1 (PRC).8 In addition, the transcription factor c-Myc emerged as an important regulator of mitochondrial gene expression. 9,10

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

“…57,58 It is possible that short-term FoxO activation favors protective antioxidant gene expression, but more prolonged ROS challenge might lead to reduced mitochondrial function as a feedback mechanism at the cost of butyrate utilization. The contention that cGMP promotes mitochondrial biogenesis, as reported previously, 38 is ostensibly at odds with FoxO suppressing cMyc function.…”

Staying alive

“…In quiescent murine HSCs, Akt is not activated, and members of the FoxO family of transcription factors, which are important for suppressing ROS levels, 211 are localized to the nucleus. Upon cytokine stimulation of HSCs, Akt becomes activated, and FoxO proteins are exported from the nucleus to the cytoplasm.…”

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

“…Induction of FOXO3a by hypoxia might help conserve ATP by restricting cell proliferation as well as by reprogramming cell metabolism. In this regard, FOXO3a was reported to regulate oxygen consumption and reactive oxygen species (ROS) production by inhibiting mitochondrial gene expression (Jensen et al 2011;Ferber et al 2012). FOXO3a activation by hypoxia could decrease mitochondrial gene expression and mitochondria DNA copy number, which could shift cellular metabolism from oxidative phosphorylation to glycolysis and reduce oxidative stress.…”